Helping Your Immune System Help You

Self-Defense Against Infection
By Durk Pearson and Sandy Shaw

First appeared in the July 2008 issue

argely because of FDA regulatory hurdles, there are only two new antibiotics in the pipeline and no end in sight for the drought in new antibiotic developments. As a result, antibiotic-resistant infections are becoming a very serious problem, especially so if you have to go to a hospital, where these resistant “bugs” are prevalent. A very close friend of ours died recently from an infection (sepsis) that he got as a result of a catheter implanted in a hospital while being treated for cancer. He never got the chance to benefit (or not) from the cancer treatments. In our opinion, the hospital’s oversight for potential catheter-related infections, a very common occurrence, was very poor, but that is another story. The point we are making here is that you need to avoid infections, and enhancing immune surveillance to prevent them in the first place is what we consider the best strategy.

Rather than just taking supplements that are alleged to “enhance immune activity,” we strive to identify particular types of immune activity that deliver the sort of protection we’re interested in, and we then search the literature for natural substances that can safely provide that type of protection. In the case of infections, we are particularly excited by the protection provided by theanine, isoleucine, and vitamin D. We explain below.

Theanine in Tea Enhances Adaptive Immune Function in Response to Bacteria, Viruses, and Tumors

A new paper in Nutrition Reviews1 reports on the impressive, adaptive immune-enhancing activity of theanine, a unique amino acid found only (as far as is known) in tea (Camellia sinensis). Brewed tea contains millimolar concentrations of theanine.1

Theanine has been found to prime gammadelta T cells, which comprise about 2–5% of total peripheral blood T cells and which mobilize (expanding by up to 50-fold) in response to alkylamines produced by bacteria. Theanine is catabolized in the kidney, resulting in the production of ethylamine, an alkylamine* that primes the gammadelta T cells known as Vgamma2Vdelta2 T cells. Priming does not cause these cells to expand in the absence of antigen but does cause them to more efficiently expand and to produce the potent antimicrobial IFNgamma (interferon gamma) in response to microbial antigens. It is like cocking a gun: the cocking itself doesn’t result in discharge but is a necessary prerequisite for discharge. Consumption of 5–6 cups a day of tea (containing 190 mg of theanine) by human volunteers increased the capacity of Vgamma2Vdelta2 T cells to secrete IFNgamma by up to 15-fold in response to ethylamine or dead bacteria.1 As noted above, the theanine or tea containing it does not increase IFNgamma secretion (which is associated with fever and other flulike symptoms) but primes the T cells to enable them to more efficiently secrete IFNgamma in response to infection.1


*Interestingly, alkylamines are also found in apples and wine and are found in up to millimolar concentrations in urine, breast milk, and amniotic fluid. See Reference 1.


The article reported that severe combined immunodeficient mice reconstituted with human peripheral blood mononuclear cells containing Vgamma2Vdelta2 T cells were protected against death from gram-negative and gram-positive bacteria. Moreover, in the same type of mice, “adoptive transfer of Vgamma2Vdelta2 T cells enhances survival against challenge with a variety of myelomas, carcinomas, and lymphomas. Such enhancement was improved when Vgamma2Vdelta2 cells were first primed.” There are clinical trials in progress testing whether the priming of these cells (by risedronate, a bisphosphonate used to treat osteoporosis, or adoptive transfer of Vgamma2Vdelta2 cells) can effectively treat lymphomas, kidney carcinoma, and solid tumors.

Moreover, a recently published, double-blind, placebo-controlled trial of a proprietary blend of theanine and catechins reported that in healthy human subjects aged 19–70 taking the formulation for three months, the incidence of cold and flu symptoms was decreased by 30%. The authors of Reference 1 found that the protective effect was due to a 30% increase, compared to placebo, in the ability of Vgamma2Vdelta2 T cells to secrete IFNgamma ex vivo (tested outside of the body). (A disclosure, under “conflict of interest” given at the end of this review article, reports that one of the authors owns stock in the company selling the proprietary blend.)

Adaptive Immunity Prevents Growth of Occult Cancer

Another paper2 reports on explicit examinations of the adaptive immune process whereby occult cancers (small, undetectable masses of cancerous cells) are maintained in a small size. In this paper, the authors show that cancer can be prevented from growing beyond a tiny, undetectable size by T cells of the adaptive immune system. Under such conditions of “equilibrium,” loss of immune competence or of the antigenicity (ability of the immune system to recognize the tumor cells) disrupts the process and results in tumor expansion. This is thought to be the reason that some occult cancers emerge when patients have received an organ transplant and immunosuppressive therapy. The authors also propose that suppression by the adaptive immune system may account for why most older men have occult prostate cancers but only in a fraction of them does development of symptomatic prostate cancer occur.

Briefly, the experiments involved exposing mice to a cancer-causing chemical, 3’-methylcholanthrene (MCA), that resulted in the development of sarcomas in some of the mice. They found that “of 187 mice treated with low-dose MCA, 86 (46%) developed progressively growing sarcomas following depletion of CD4/CD8 cells, IFNgamma, and/or IL-12—components that participate in adaptive immunity. . . . We therefore considered the possibility that at least some of the MCA-treated wild-type mice that remained free of progressively growing tumors harboured fully transformed sarcoma cells, the outgrowth of which was immunologically restrained.” In the MCA model, transformed cells emerge exclusively at the site of injection. “Examination of the injection site in 129/SvEv mice treated with 25 µg MCA revealed the presence of small 2–8-mm masses that became palpable within 150 days of MCA injection but did not change in size during an additional 150 days.”

The authors concluded that net tumor cell expansion was being immunologically restrained. They concluded that “maintaining cancer in an equilibrium state may represent a relevant goal of cancer immunotherapy in which augmentation of adaptive tumour immunity could result in improved tumour control” of some kinds of cancers.

The Essential Amino Acid Isoleucine Induces Antimicrobial Peptides in Epithelial Tissues

An exciting paper3 from 2000 that has seemingly been forgotten reported that the essential amino acid isoleucine induces beta-defensins (antimicrobial peptides) in skin, airway, gut, and urogenital tract epithelial tissues, thus providing important protection against microbes by drilling holes in their membranes. “In addition to their direct antimicrobial activities, beta-defensins are chemotactic [attractive] for memory T cells, suggesting that they play an important role in the integration of the innate and acquired [adaptive] immune responses. . . . Isoleucine induced the expression of the beta-defensin 10- to 12-fold with peak activity between 3.12 µg/ml and 12.5 µg/ml.”1

Moreover, the authors found that isoleucine was highly specific in its induction of beta-defensin, as other amino acids did not do so. Isoleucine acts as a signal for the presence of potentially harmful microbes.1 It is an alkylamine1 (as is theanine, see above) and, though they didn’t test for it here, isoleucine probably primes the gammadelta T cells in the same way as theanine. The researchers note that “alkylamines are produced in vitro by a number of pathogenic bacteria including Salmonella typhimurium, Listeria monocytogenes, and Yersinia enterocolitica.

Vitamin D Against Infections

A recent paper4 reports that bacterial invasion is recognized in injury and stimulates the production of antimicrobial peptides through a vitamin D-dependent mechanism. The authors discovered this via an investigation of the expression of genes influenced by vitamin D3 (1,25D3, the active form) in the setting of wound repair.

They found that “injury triggers a local increase in 1,25D3 signaling in skin.” Then they found that 1,25D3 stimulated an increase in the expression of TLR2 [toll-like receptor 2] and CD14, microbial pattern recognition receptors, and cathelicidin, an antimicrobial peptide.

A somewhat earlier paper5 found that toll-like receptor activation in human macrophages caused an upregulation of the expression of the vitamin D receptor and the vitamin D1-hydroxylase genes that resulted in the induction of the antimicrobial peptide cathelicidin. The cathelicidin killed intracellular Mycobacterium tuberculosis. (The action of the vitamin D receptor in the killing of the tuberculosis microbe links the long-standing knowledge that tuberculosis patients do better when exposed to sunlight.) The authors suggest that innate differences in the ability of human populations to produce vitamin D “may contribute to susceptibility of microbial infections.”


We strive to identify particular types of
immune activity that deliver the sort of
protection we want, and we then
search for natural substances that can
safely provide that type of protection.


As part of their study,5 the authors found that “Addition of 1,25D3 to primary human macrophages infected with virulent M. tuberculosis reduced the number of viable bacilli . . . By demonstrating that TLR stimulation of human macrophages induces: (i) the enzyme that catalyzes conversion of 25D3 to active 1,25D3; (ii) the expression of the vitamin D receptor (VDR); and (iii) relevant downstream targets of VDR (including cathelicidin), the present results provide an explanation for the action of vitamin D as a key link between TLR activation and [certain] antibacterial responses in innate immunity.”

Finally, in another report,6 the vitamin D receptor was found to be required for the development of natural killer T cells, which are important cells in immune regulation, tumor surveillance, and host defense against pathogens.

Why Vitamin K Should Be Taken with Vitamin D

We add this section because, while vitamin D and calcium supplements increase the absorption of calcium, adequate vitamin K is essential to ensure that the calcium ends up in bone rather than as calcium deposits in blood vessels. The proper regulation of calcium is carried out by osteocalcin, a hormonelike peptide produced by osteoblasts (bone cells that manufacture bone).7 Vitamin K is required for the conversion of the preosteocalcin molecule to osteocalcin, its active form. (In fact, mice with the osteocalcin gene knocked out have abnormally high amounts of visceral fat, and early clinical observations revealed “significantly lower serum OC [osteocalcin] values in patients suffering from type 2 diabetes compared to healthy persons, and restoration of glycemic control resulted in increased OC levels.”7

While the recommended daily allowance of vitamin K is 1 µg/kg of body weight per day, that is based only upon adequate levels for proper blood clotting and not on the amount required for optimal bone formation or to prevent calcium deposition in blood vessels by carboxylating osteocalcin. “There is some evidence that the current RDA may not be sufficient to maximally carboxylate [activate] this protein [osteocalcin].”7 Most dietary vitamin K comes from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola, and olive); however, the bioavailability from vegetables is relatively poor. “The 2005 Dietary Guidelines for Americans recommends 3 cups/week of dark green vegetables, which contain about 100 to 570 µg/serving of vitamin K.”8 However, what is actually absorbed is unclear and likely to be much less.

Studies such as that of Sokoll et al.9 found that increasing vitamin K intake from 100 to 420 µg/day resulted in a significant decline in the percentage of uncarboxylated osteocalcin within five days, suggesting that the “normal” intake of vitamin K in the North American population is not sufficient to maximally carboxylate osteocalcin.

References

  1. Bukowski and Percival. L-Theanine intervention enhances human gammadelta T lymphocyte function. Nutr Rev 66(2):96-102 (2007).
  2. Koebel et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903-6 (2007); also see commentary on this paper in same issue.
  3. Fehibaum et al. An essential amino acid induces epithelial beta-defensin expression. Proc Natl Acad Sci USA 97(23):12723-8 (2000).
  4. Schauber et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 117(3):803-11 (2007).
  5. Liu et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311(5768):1770-3 (2006).
  6. Yu and Cantorna. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci USA 105(13):5207-12 (2008).
  7. Booth and Suttle. Dietary intake and adequacy of vitamin K. J Nutr 128: 785-8 (1998).
  8. Johnson. Influence of vitamin K on anticoagulant therapy depends on vitamin K status and the source and chemical forms of vitamin K. Nutr Rev 63(3):91-7 (2005).
  9. Sokoll et al. Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr 65:779-84 (1997).

©2008 by Durk Pearson & Sandy Shaw

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